The title of this Program Projects Application "Excitatory Transmitters, Memory, Aging and Dementia" accurately identifies the several closely related themes that the proposed research addresses. The principal excitatory neurotransmitters in the mammalian CNS are glutamate (Glu) and acetylcholine (ACh). Both of these transmitters act at multiple receptor subtypes; either hyperstimulation or blockade of either Glu or ACh receptors is associated with neuropathological changes in animal brain and/or memory/cognitive disturbances in animals and humans. Within the framework of two cores and seven separate projects, the Principal Investigator, 11 Co-investigators and 7 Consultant/Collaborators will study mechanisms by which excitatory transmitters, either in early adulthood or old age, can contribute to normal memory/cognitive functions or to memory/cognitive impairment, neuronal degeneration and cell death. A major emphasis of the research will be on identifying mechanisms of neuronal degeneration that might help explain the pathophysiology of Alzheimer's disease. One project pertains to human subjects and will involve the measurement of excitotoxic amino acids (Glu, aspartate, glycine, cysteine) in cerebrospinal fluid and blood of clinically characterized AD patients in different stages of the illness. The remainder of the proposed research comprises either in vivo or in vitro animal experiments. A wide range of neurochemical, neuropharmacological, neurophysiological, neurobehavioral, neurohistological and molecular biological or immunobiological methods will be employed, including the use of nucleotide and immunological probes for studying subtypes of excitatory amino acid and muscarinic cholinergic receptors which have recently been cloned.